Transdermal drug delivery (TDD) is a non-invasive, convenient and painless dosage form which offers numerous clinical benefits such as steady blood-level profile, reduced systemic side effects, and often an improved efficacy and patient compliance. But TDD is not clinically justified for all drugs and is currently a limited technology suitable for a niche set of drugs. Current innovations in TDD mostly occur in system and formulation solutions, where system innovations refer to various approaches to increasing drug flux across the skin. Stratum comeum, the outermost layer of the skin, prevents passive permeability of most compounds including drugs, except for those of low molecular weight and lipophilic. Therefore, it is impossible to transdermally deliver proteins, vaccines and most biopharmaceuticals, without a chemical or physical method of enhancing the passive diffusion mechanism.
Much research has been going on in developing transdermal technologies that utilize mechanical energy to increase drug flux across the skin, such as iontophoresis, sonophoresis, electroporation and thermal energy. Another-area of research is in creation of micropores in stratum comeum to provide a path of lower resistance to diffusion of drug molecules. These devices include microstructures, usually referred to as microneedles, (also referred to as microprojections, microtips, etc.), made of various materials such as metal, PMMA, glass, silicon, etc.
Some advantages of silicon based microneedles lie in that they are realized using traditional CMOS processing techniques, which makes them suitable for integration with other components to facilitate added functionality (iontophoresis, thermal components, etc.). A limitation of known microneedles lies in the complexity of known manufacturing processes, which results in long and challenging product development, and often requires specialty tools. This ultimately results in low yield manufacturing process, lack of reproducibility and high cost.
Many existing methods and systems for drug delivery include microneedles to break the skin as the barrier and to enhance passive diffusion of drugs across the stratum comeum. Fundamentally, these systems typically incorporate microneedles for micropore formation, but technologically vary in how the microneedles are realized, and in how drug is delivered into the patient. For example, U.S. Pat. No. 6,767,341 issued to Cho describes an array of hollow microneedles fabricated in a silicon substrate using conventional semiconductor manufacturing methods.
Alignment of the hole to the microneedle is another limiting factor. Typically, back-to-front alignment allows for greater than 5 microns tolerance, which results in a large error when attempting to precisely place the hole on a side of the microneedle. Forming the hole through a microneedle additionally compromises the mechanical robustness of the microneedle, which represents a significant issue because the microneedles must ultimately penetrate into the patient, and it is unacceptable for microneedles to break inside the patient and remain inside the patient's body. In addition, microfluidic components are often required for complete drug delivery solutions. From the silicon processing and system integration standpoint, this becomes a highly involved manufacturing process and consequently not a high volume/high yield, low cost scenario, and existing systems thus lack economical viability.
U.S. Pat. No. 6,689,101 issued to Connelly et al. relates to a variety of devices that incorporate microneedles realized using different processing techniques in a variety of materials. The described delivery mechanism involves an array of orifices through an array of skin penetrating members and it fundamentally suffers the same drawbacks as those described in the analyses above. Similarly, U.S. Pat. No. 6,611,707 issued to Prausnitz at al. describes a substrate to which a plurality of microneedles are attached or integrated, and at least one reservoir containing the drug, which communicates with microneedles via additional microfluidic components. In addition, U.S. Pat. Nos. 6,558,361 and 6,533,949 describe methods for processing a wafer to form a plurality of hollow microneedles projecting from the substrate. Issues such as alignment, reproducibility, system complexity, reliability, throughput and cost are as present as in all above mentioned references. Also, U.S. Pat. No. 6,406,638 is another example of a microneedle design and fabrication process that does not clearly exhibit economical viability.
Thus, there is a need for microneedles which can be produced in a precise and economically viable manner while achieving suitable robustness for intradermal delivery of substances.